This invention provides a method for selecting compounds potentially useful for the treatment and prevention of pre-cancerous and cancerous lesions in mammals.
For many years, researchers have sought compounds that selectively treat neoplastic cells without substantial growth-inhibiting adverse effects on normal cells. Conventional cancer chemotherapeutics--regardless of the type of cancer against which they have been directed--share one common feature: conventional compositions (e.g., herceptin, taxol, cisplatin, tamoxifen etc), to the extent they have any substantial effects on neoplastic cells--virtually always have significant adverse effects on normal tissues. Many of the side effects are debilitating and life-threatening. Thus, conventional chemotherapeutics are typically administered only after the neoplasia has significantly progressed to the stage where the drug side effects clearly outweigh the risks of no chemotherapy.
Conventional chemotherapeutics also typically are used to treat fairly specific types of neoplasias. For example, leuprolide is commonly prescribed to treat advanced prostate cancer, but not colon or lung cancers. Compositions with activities against broader ranges of neoplasias are desired.
Pamukcu et al., in U.S. Pat. No. 5,401,774, compounds such those now known as exisulind are disclosed for anti-neoplastic purposes. Contrary to conventional chemotherapeutics, such compounds are selective against neoplastic cells as opposed to normal cells. Thus, such compounds can be administered on a chronic basis without the side effects normally associated with conventional chemotherapeutics. In addition, because of their safety profile, such compounds can be administered at the earliest stages of disease. Thus, new compounds have become recognized as a new class of antineoplastics known as selective apoptotic anti-neoplastic drugs ("SAANDs").
Besides outstanding safety advantages over conventional chemotherapeutics, SAANDs also have a wider range of therapeutic application compared to conventional chemotherapeutics. For example, the first SAAND, exisulind, has been reported to have anti-neoplastic effects on colon, breast, lung, prostate, kidney, and melanoma neoplasias. It also has effects on other neoplasias.
SAANDs have the further advantage over anti-neoplastic NSAIDS (e.g., sulindac) because, unlike NSAIDs, SAANDs do not inhibit COXI or II enzymes. Inhibition of COX I and/or COX II enzymes (e.g., by indomethacin, celecoxib and other NSAIDs) lead to considerable side effects when taken on a chronic basis. In addition, COX inhibition is unnecessary for anti-neoplastic efficacy. Not surprisingly, not all COX I and COX II inhibitors (e.g., carprofen) also have been demonstrated to have significant anti-neoplastic activities. The side effects of COX I and COX II inhibitors include gastric irritations that can lead to severe ulceration, and kidney toxicities. Since SAANDs antineoplastic therapy is enhanced with chronic or long-term administration, the COX inhibitors--to the extent any exhibit anti-neoplastic properties--are inappropriate simply because of safety considerations, since few patients can realistically take COX inhibitors chronically or long-term. For inflammation, COX inhibitors are commonly used only on a short-term or acute basis as a result.
How SAANDs act without the side effects of COX inhibitors (or the even more severe side effects of conventional chemotherapeutics) remained a mystery until recently. As reported in U.S. Pat. No. 5,858,694, SAANDs work, in part by the inhibition of PDE5, which appears to be a necessary part of how SAANDs induce apoptosis (a form of cell death) in neoplastic, but not in normal cells. It was also discovered that SAANDs work by increasing cGMP and reducing cAMP in neoplastic cells, also as reported in the '694 patent.
However, it was later discovered that some PDE5 inhibitors did not singly (i.e. without other compounds) induce apoptosis (see, e.g. U.S. patent application Ser. No. 09/173,375 filed Oct. 15, 1998). In the '375 application, the discovery of a new cGMP-specific PDE found in neoplastic cells was first reported. One observation that separated anti-neoplastic PDE5 inhibitors from other PDE5 inhibitors was that the anti-neoplastic PDE5 inhibitors inhibited the new cGMP-specific PDE, whereas the other PDE5 inhibitors (e.g., sildenafil) had little relative effect. This observation, as disclosed in the '375 application, led to more accurate drug discovery screening methods to identify anti-neoplastic PDE5 inhibitors (i.e. additional SAANDs).
However, more accurate and alternative methods to evaluate and identify compounds for their usefulness as SAANDs are desired.